September 20, 2012

Researchers Track Gene Expression To Create Atlas of Human Brain

A research team from the Allen Institute for Brain Science reports that human brains share a consistent genetic blueprint and possess enormous biochemical complexity. The findings, published in Nature, stem from the first in-depth and large-scale analysis of the vast data set publicly available in the Allen Human Brain Atlas.

The Allen Human Brain Atlas fully integrates different kinds of data across different scales of brain exploration in an open, public online resource. It details genes at work throughout the human brain with data incorporated from magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) as well as histology and gene expression data derived from both microarray and in situ hybridization approaches.

The results of this new study are based on extensive analysis of the Allen Human Brain Atlas, specifically the detailed all-genes, all-structures survey of genes at work throughout the human brain. This enormous dataset profiles 400 to 500 distinct brain areas per hemisphere using microarray technology. It comprises more than 100 million gene expression measurements covering three individual human brains to date, including two "clinically unremarkable" brains donated by a 24-year-old and 39-year-old man, and half a brain from a third man.

Among other findings, these data show that 84% of all genes are expressed somewhere in the human brain and in patterns that are largely similar from one brain to the next.

"This study demonstrates the value of a global analysis of gene expression throughout the entire brain and has implications for understanding brain function, development, evolution and disease," said Ed Lein, Ph.D., Associate Investigator at the Allen Institute for Brain Science and co-lead author on the paper.

"These results only scratch the surface of what can be learned from this immense data set. We look forward to seeing what others will discover."

The team expects their work to serve as a baseline against which others can compare the genetic activity of diseased brains, and so shed light on factors that underlie neurological and psychiatric conditions.

"The human brain is the most complex structure known to mankind and one of the greatest challenges in modern biology is to understand how it is built and organized," said Seth Grant, a professor of molecular neuroscience at Edinburgh University who worked on the brain map.

"This allows us for the first time to overlay the human genome on to the human brain. It gives us essentially the Rosetta stone for understanding the link between the genome and the brain, and gives us a path forward to decoding how genetic disorders impact and produce brain disease," he said.

The two full brains came from men of similar age and ethnicity, and the pattern of gene activity was so similar that the team suspects there may be a common blueprint for the expression of genes in the human brain. Work is ongoing with donated tissues from both sexes being used to check the consistency of that genetic blueprint among people with healthy brains. Researchers suspect that there will probably be some differences between expression patterns in male and female brains, as suggested by previous work the Institute has done with rodents.

Similar gene atlases have previously been constructed for rodents, but the shortage of donated human brains, coupled with the destructive nature of the tests and the 1,000-fold increase in brain size, have made the construction of a human equivalent more challenging.

Comparisons of the human and rodent brain atlases may help pharmaceutical companies develop better psychiatric medicines. Many treatments do well in mouse models and fail in human trials. The team says that knowing how the two systems differ on a fine-grained level may help avoid expensive failures.

The atlas, which overlays the genetic results onto a 3D image of the brain, is freely available online for researchers to use.

Grant said that future studies will look to connect the genetic brain atlas with other genetic studies or brain scans of abnormal or diseased brains. That could highlight genes that play a role in brain conditions and point the way to drug treatments that either suppress or ramp up gene activity.

Clyde Francks at the Max Planck Institute for Psycholinguistics in the Netherlands is already using genetic data from the Allen Institute for Brain Science to pinpoint genes that give rise to brain asymmetries in a set of 1,300 Dutch students.

The Allen Institute researchers have come up with some interesting nuggets of insight hidden within their own data set. For example, when they looked at the gene expression data from the cortex — the outer shell of the brain that is generally related to higher-level thought and cognition — they found a surprising amount of uniformity in the genes that were expressed there when compared to other areas that sit below the cortex.

This may suggest both that the cortex is easily expandable — perhaps explaining its rapid evolution in primates — and that the cortex is relatively uncomplicated simply because of how it is genetically programmed. Instead, aspects like the delicate balances of activity from different types of cells may distinguish the functions of different cortical areas.